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Acta Neuropathol. 2019 Jul;138(1):23-47. doi: 10.1007/s00401-019-02007-x. Epub 2019 Apr 11.

Binding of α-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes.

Author information

1
Department of Clinical Pathology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. juan.reyes@liu.se.
2
Department of Clinical Pathology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
3
Department of Molecular Neurology, University Hospital Erlangen, Erlangen, Germany.
4
Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
5
Section of Geriatrics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
6
Department of Clinical Pathology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. martin.hallbeck@liu.se.

Abstract

The intercellular transfer of alpha-synuclein (α-syn) has been implicated in the progression of Parkinson's disease (PD) and multiple system atrophy (MSA). The cellular mechanisms underlying this process are now beginning to be elucidated. In this study, we demonstrate that the gap junction protein connexin-32 (Cx32) is centrally involved in the preferential uptake of α-syn oligomeric assemblies (oα-syn) in neurons and oligodendrocytes. In vitro, we demonstrate a clear correlation between Cx32 expression and oα-syn uptake. Pharmacological and genetic strategies targeting Cx32 successfully blocked oα-syn uptake. In cellular and transgenic mice modeling PD and MSA, we observed significant upregulation of Cx32 which correlates with α-syn accumulation. Notably, we could also demonstrate a direct interaction between α-syn and Cx32 in two out of four human PD cases that was absent in all four age-matched controls. These data are suggestive of a link between Cx32 and PD pathophysiology. Collectively, our results provide compelling evidence for Cx32 as a novel target for therapeutic intervention in PD and related α-synucleinopathies.

KEYWORDS:

Alzheimer’s disease (AD); Cell-to-cell transfer; Cx32; GJB1; Gap junction proteins; Multiple system atrophy (MSA); Parkinson’s disease (PD); Prion-like transfer; alpha-Synuclein (α-syn)

PMID:
30976973
DOI:
10.1007/s00401-019-02007-x

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